The present application is a subsequent patent application of CN200510040865.1, CN200610126892.5, CN200910052231.6, CN201310205609.8, CN201310352414.6, CN201310364101.2, CN201410346419.2, U.S. Pat. No. 8,039,511B2, U.S. Pat. No. 8,410,170B2, EP06817815.1, CA2630262 and JP5308160.
Cancer is a major disease which threatens human health. The treatment of cancer is always closely concerned all over the world. Chemotherapeutic drugs can nonspecifically block cell division, thus resulting in cell death; however, they also destroy normal cells of a body when killing tumor cells. It is an urgent need to reduce side effects of chemotherapeutics and enhance therapeutic effects of the chemotherapeutics.
Anti-cancer drugs, which effect or influence DNAs, such as alkylating agent anticancer drugs, are of broad-spectrum anti-tumor effect, while of poor selectivity as its main drawback. It is of strong toxicity to vigorous growing normal cells, such as bone marrow, gastrointestinal epithelium and reproductive system, and can cause leukopenia and thrombocytopenia, aplastic anemia, or whole blood inhibition. Gastrointestinal reactions comprise nausea, vomiting, inflammation and ulcers, etc. For example, inhibition of hematopoietic function of bone marrow, gastrointestinal reactions and strong toxicity to heart are the major adverse reactions of antibiotic antitumor drugs. Patients are in an urgent need of reducing the toxicity of anticancer drugs of this type, reducing clinical doses, and finding a reliable combination regimen.
Cytotoxic drugs often have limited therapeutic spectrum, and can lead to treatment-related adverse reactions. While targeting specific pathways can prevent tumor growth as well as reduce toxicity to normal cells. The development of anticancer drugs has been transited from random selection by experience to reasonable drug development targeting specific cell dysfunction according to mechanism. Many drugs developed by targeting strategy have been used in clinical and achieved good results. With the development of molecular biology, tumor molecular targeted therapy research based on tumor molecular mechanisms has been significantly progressed. Currently, protein kinase inhibitors are the focus of drug research for cancer targeted therapy, in which survival and proliferation of tumor cells and progression of disease are affected by blocking molecule signaling pathways in cells. However, kinase inhibitors used alone are of limited efficiency and there are some side effects. Therefore, the clinical treatment of cancer is in urgent need of drug combinations which are of significant therapeutic effects and low toxic side effects.
Prostate cancer (PCa) is the most common malignant tumor of reproductive system in male, incidence of which now ranks the third in male cancer, and rapidly increases in recent years. Prostate cancer is seriously affecting the life quality and expectancy of domestic male citizens over 50 years old. Because of inadequate awareness and attention to prostate cancer, early examination, early detection and early treatment (while in developed countries, examinations about prostate cancer are must projects in health check of elderly male citizens) of prostate cancer are seldomly conducted, and most of discovered cases of prostate cancer in China are advanced cases, which brought great difficulty for the effective treatment, and has become one of the key areas of concern of Urology.
Most prostate cancer patients in the early and medium-term onset can be treated by surgery, radiation therapy and drug treatment, while patients in advanced stage can be treated by hormonal therapy or orchiectomy treatment. In terms of therapeutic efficacy and side effects, all of the methods are of some limitations. For example, after surgery, side effects such as difficulty in urinating and sexual disorders occur in most patients, which would likely last for several years.
Advanced stage prostate cancer patients cannot be treated by excision, so endocrine therapy is the main treating method. The main method of endocrine treatment comprises drug or surgical castration, androgen blockade to target cells, 5α-reductase inhibitors, anti-adrenal secretion drugs, etc. Castration or combination therapy are initially effective for most patients, but after 14 to 30 months, lesions in almost all the patients will gradually develop into hormone-independent prostate cancer, which shows resistance to endocrine therapy. During early stage of hormone-independence, second-line endocrine therapy is still valid in some patients, which is known as androgen-independent prostate cancer (AIPC), while prostate cancer, in which the second-line endocrine therapy is invalid or lesions continue to develop during second-line hormonal therapy, is known as Hormone Refractory Prostate Cancer (HRPC). The mechanisms of AIPC and HRPC are still unknown at present, and there is no effective therapeutic, which makes it a worldwide problem as well as the main cause of death of patients with prostate cancer. It is the key point and challenge to look for new anti-cancer drugs for enhancing the effect of endocrine therapy, thereby effectively delaying or reversing AIPC and HRPC.
Isothiocyanates (ITCs) are derived from vegetables which are most commonly consumed by human. Domestic and foreign colleagues have studied them for decades, and found by in vivo animal experiments that ITCs are effective in preventing many types of cancers, while the epidemiological studies also confirmed that the intake of vegetables containing ITCs can effectively reduce the risk of cancer in human being. Basic studies have shown that isothiocyanates are dual inhibitors which can inhibit abnormal DNA methylation as well as histone deacetylase, and useful for the treatment and prevention of cancers.